Polyvinylpyrrolidone is the homo-polymer of 1-ethylenyl-2-pyrrolidinone also known as 1 vinyl-2-pyrrolidinone polymer of the following formula: ##STR1## a common name for this chemical substance is povidone and the compound is sometimes designated as PVP.
Povidone is a synthetic polymer consisting essentially of linear 1-vinyl-2-pyrrolidinone groups which have been polymerized into polymer chains of various molecular weights, generally having mean molecular weights ranging from about 10,00 to 700,000 although polymers of both lesser and higher molecular weights are known.
Providone is available as an article of commerce, either as a dry powder or in aqueous solution for use in a wide variety of chemical, pharmaceutical and food manufacturing processes as well as special industrial compositions such as inks, paints and emulsions, cosmetics and germicidal products. Povidone is used for example in the manufacture of adhesives to improve strength and toughness; in cosmetic products to condition and protect skin and hair; in pharmaceutical manufacture as a tablet binder, coating agent, dispersant and protective colloid; in the manufacture of plastics as a pigment dispersant, bonding agent, and stabilizer; in paper manufacture to increase strength as well as a coating polymer and in synthetic fibers to improve dye receptivity. It is also widely employed in inks, lithography, detergents and soaps, textiles, agricultural products and as a clarifying aid.
Underriding the overall use of povidone in manufacture and formulation of different compositions is its contribution to the viscosity of the fluid medium being used. The viscosity contribution of povidone ranges from high viscosity to low viscosity and is a function of the average molecular weight of the polymer. Povidone is classified by K-values which are assigned to the various povidone polymers. These constants, i.e., K-values, are derived from viscosity measurements in accord with the well known Fikentscher's formula and the smaller the K-value, the lower the intrinsic viscosity of the polymer.
The more common commercially available povidone polymers have K-values of K-14, K-30, K-60 and K-90, and in aqueous solutions, povidone K-15 and povidone K-30 have little effect on viscosity in concentrations below 10%, whereas povidone K-60 and povidone K-90 have considerable influence on the flow properties of a solution at such concentrations. While the viscosity effect of povidone is virtually unchanged by pH, concentrated hydrochloric acid and strong alkali have been shown to influence the viscosity of povidone. Moreover, certain organic solvents have a particular effect on the viscosity contribution of povidone, the intensity of which is related to the polarity of the particular organic solvent.
Povidone forms molecular adducts or complexes with many substances to result in a solubilizing action for certain materials but also a precipitation effect for others. The povidone polymer reacts with poly-acids to form complexes that are generally insoluble in water but these may be solubilized by special treatment of the formed insoluble polymer. Cross-linkage of the povidone polymer is influenced by many diverse factors as for example, actinic light, diazo compounds, oxidizing agents and heat. Cross-linking of the povidone polymer is a serious limitation to its use since the povidone polymer is now altered into an aqueous insoluble form.
It is well known that povidone and its solutions are capable of supporting microbial growth as for example, bacteria, viruses, molds and yeast. While the usual preservatives such as benzoic acid, sorbic acid and the esters of parahydroxybenzoic acid may be used as germicides for povidone preparations, these present special limitations because of their less than broad antimicrobial spectrum and their known allergenicity. While aqueous solutions of povidone are known to be relatively stable to heat, and short interval autoclaving has been used to sterilize povidone preparations, this use of heat is also known to cause degradation of the polymer. Thus for example, povidone which is stable to moderate heat will darken in color and decreases in water solubility when heated to about 150.degree. C. The presence of certain substances in the povidone solution will accelerate cross-linking at even lower temperatures. When a povidone solution is heated to 100.degree. C., in the alkaline pH range, the polymer becomes permanently altered to be irreversibly insoluble. Similar cross-linked changes occur when alkaline sodium phosphate buffers are used and when an oxidizing agent such as ammonium persulfate is added to a povidone solution, cross-linking gel formation occurs in about 30 minutes when the combination is heated at moderate temperatures of about 90.degree. C.
The cross-linking of the polymer caused by heat, oxidizing agents, salts and other substances presents special problems in the manufacture and processing of certain compositions containing povidone, when these povidone solutions are intended for parenteral use, since the formed insoluble cross-linked povidone may initiate thrombotic episodes and other noxious events. When povidone is used in the manufacture of those preparations requiring sterilization but containing oxidizing agents or other oxygen sources, then similar incompatibility occurs to limit the use of povidone in the preparations.
Gamma radiation is known to be an effective sterilizing process but is notoriously unsuited for use with povidone polymers. The literature is replete with references to the particular degradative effects of cross-linkage occurring when povidone is exposed to even minimal gamma radiation dosage. The various aspects of radiation induced changes in aqueous polymer solution have been ascribed to free radical formation and subsequently initiated chemical changes. The actions of radiation on povidone, together with radiolysis products formed in the composition, results in macroradical polymer chain formation and these macroradicals further inter-react so that the ultimate effect of radiation is either cross-linkage gelation or chain scission.
Gamma irradiation interacts with target atoms to cause one or more of three different actions, namely photo-electric effects, Compton scattering, and pair-production. As the energy dose of the gamma irradiation increases, the particular predominant effect succeeds to the next dose related responsive stage, from the photo-electric stage to the Compton scattering stage and finally to the pair-production stage. Both the photo-electric and Compton scattering effects produce highly ionizing electrons which are uniformly distributed throughout the radiation target and these influence the formation of free radicals and ionic reactions. It is the combination of these reactions in the vicinity of contaminent microorganisms that brings about the lethal efficacy or sterilizing properties of irradiation processes.
When povidone solutions are irradiated with gamma radiation, gelation occurs when the concentration of povidone in solution is above the critical limit of from 0.3% to 1% by weight of povidone, dependent upon the molecular weight. For the lower molecular weights of K-30 and below the critical concentration factor is between 0.5% and 1% by weight while for values above K-30 this critical concentration is between 0.3% and 0.5%. Below this critical concentration limit, macrogelation to form a wall-to-wall gel, is not readily observed. For intermolecular cross-link formation, the polymer chains must be in close proximity to each other. In dilute solutions, the mobility of polymer chains is increased and while some chains are deactivated by the radiolysis products of water before they achieve intermolecular linkage, the increased mobility of the polymer chain will increase the probability of intermolecular cross-linking when irradiated. Furthermore, in dilute solutions the smaller polymer chains react with the radiolytic by-product of water to reduce gel formation. Thus gelling does not occur below the critical concentration limits.
In dilute poly-electrolyte solutions, the polymer products become ionized to increase the overall gelation effect of the polymer. Oxidative degradation is associated with a decrease in viscosity that is generally observed in the early stages of the irradiation of povidone, and a subsequent increase in viscosity occurs as intermolecular cross-linking overtakes the first phases of intramolecular linking and chain scission. As the intermolecular cross-linking progresses under further radiation dosage, the overall effect is a decrease in viscosity through microgel unit formation and the solution becomes turbid.
The sensitivity of povidone to low doses of gamma radiation is so pronounced that adverse gelation cross-linkage effects are observed after irradiation with doses as low as 0.1 kilrad, when the particular critical concentration of povidone in solution is exceeded. The use of povidone in most industrial, agricultural and pharmaceutical manufacturing procedures exceeds the critical concentration limits established for povidone. The critical concentration level for povidone is further adversely modified by ionizing solutions, oxidizing agents and pH. This destructive, degradative response of povidone to gamma radiation which destroys its desirable properties in the formulation eliminates the use of gamma radiation as a means to render povidone and povidone-containing compositions free of microbial contamination.
Thus, attempts to produce sterilized povidone-iodine by irradiation of the povidone prior to formation of the povidone-iodine has been unsuccessful because of the above described undesirable action of the irradiation on the povidone.
On the other hand, the sterilization of povidone-iodine after formation thereof is found to be unsatisfactory because the irradiation has the effect of decreasing the amount of available iodine with consequent reduction in antibacterial activity.